Process for producing amidine sulfonic acid intermediates for guanidines

ABSTRACT

An efficient synthesis of quanidines, e.g. of the formula (III), by oxidizing a thiourea, e.g. of the following formula (II): ##STR1## with H 2  O 2  and a molybdenum catalyst to yield an aminoiminomethane sulfonic acid which can then be reacted with an amine followed by optional transamination steps.

This application is a division of U.S. Ser. No. 934,376 filed Nov. 24,1986 now U.S. Pat. No. 4,781,866 which is a division of U.S. Ser. No.868,231 filed May 28, 1986, now U.S. Pat. No. 4,656,291, which is acontinuation-in-part of U.S. Ser. No. 711,948 filed Mar. 15, 1985, nowU.S. Pat. No. 4,656,270.

BACKGROUND OF THE INVENTION

As reported in Chemical Week on Sept. 18, 1985 at pages 13-14, there isa considerable need for a simple, inexpensive and non-polluting route toguanidines. Guanidines constitute an important class of organiccompounds useful for various medical and agricultural purposes includinghypoglycemic agents for the treatment of diabetes.

The present invention also relates to the synthesis of guanidinecomopounds such as the anti-diabetic compound linogliride orN-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-4-morpholinecarboximidamideand includes synthetic steps and intermediates.

Linogliride fumarate (CAS Registry No. 78782-47-5) is a hypoglycemiccompound and is disclosed in U.S. Pat. No. 4,211,867. It is an object ofthe present invention to provide a high yield, facile and shortsynthesis of linogliride with by products and reagents which arecomparatively safe and easily handled.

At column 11 of U.S. Pat. No. 4,211,867 there is described a method ofmaking a N,N'-disubstituted guanidine intermediate by reacting anN-substituted thiourea with an alkylating agent to produce thecorresponding alkylthio compound which is then reacted with an amine todisplace mercaptan. Such a route has the disadvantage of removal anddisposal of malodorous mercaptans.

Oxidations of thioureas are found in U.S. Pat. Nos. 4,210,658; 4,275,896and 4,381,395, U.K. Pat. No. 1,586,258; U.S.S.R. Pat. No. 178,803published Feb. 3, 1966 and by W. Walter and G. Randau in Liebigs Ann.Chem. 722, pages 98-109 (1969).

SUMMARY OF THE INVENTION

A method has been devised whereby a thiourea is oxidized in high yieldsto an amidine sulfonic acid by using a molybdenum catalyst such as Na₂MoO₄ with H₂ O₂ as the oxidizing agent. Such sulfonic acids have beenfound to be excellent intermediates for the preparation of guanidinessuch as N-phenyl-4-morpholinecarboximidamide, which is itself aprecursor for the preparation of linogliride.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, a thiourea is oxidized with hydrogenperoxide in the presence of a molybdenum catalyst to yield an amidinesulfonic acid. Thus, an acid of the following formula (I): ##STR2## isproduced by oxidizing a thiourea of the following formula (II) with H₂O₂ in the presence of a Mo catalyst: ##STR3## wherein for (I) and (II),R¹, R² and R³ are independently inorganic or organic groups such ashydrogen, NH₂, perhaloalkyl, perhaloaryl, NO₂ or a saturated orunsaturated alkyl, substituted alkyl, cyclic alkyl, substituted cyclicalkyl, aryl, substituted aryl, heterocyclic or substituted heterocyclic.Preferably, R¹ and R² are both not NH₂ or NO₂.

As used herein, "alkyl" is any straight or branched hydrocarbon group ofthe formula C_(n) H_(2n+1) ; "cyclic alkyl" is a hydrocarbon grouphaving at least one ring; "aryl" is an aromatic hydrocarbon ring;"heterocyclic" is an aromatic or non-aromatic ring having at least oneheteroatom such as N, S or O; and "substituted" is any of such groupswhere one or more hydrogen atoms are replaced by one or more saturatedor unsaturated organic or inorganic groups such as alkyl, cyclic alkyl,aryl, heterocyclic, halogen such as F, Cl, Br or I, NH₂, NO₂, OH,alkoxy, alkylthio, aryloxy, arylthio, alkanoyl, alkanoyloxy, aroyl,aroyloxy, azido, amido, alkylamino, dialkylamino, arylamino,alkylarylamino, diarylamino, alkanoylamino, alkylsulfinyl,alkylsulfenyl, alkylsulfonyl, alkylsulfonylamido, azo, benzyl, carboxy,cyano, guanyl, guanidino, imino, phosphinyl, phosphorous, silyl, thioxo,ureido or vinylidene or where a carbon atom is replaced by oxygen orsulphur. Such are merely examples of the organic groups which can beused with the invention. Preferably, R¹, R² and R³ contain no moietieswhich are oxidizable with H₂ O₂ under mild conditions or, if so, resultin a desired group of a higher oxidation state than the startingmaterial. In particular, R¹ is hydrogen; or R¹ and R² are hydrogen; orR¹, R² and R³ are hydrogen; or R¹ and R³ are hydrogen; or R¹ is hydrogenand R² and R³ are joined to form a --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --group which may be unsubstituted or substituted.

Amidine sulfonic acids of the formula (I) may be used as intermediatesto prepare guanidines by reaction with NH₃ or a primary or secondaryamine or a cyclic amine having an NH group such as morpholine. Thereaction of (I) with the amine may be carried out with a molar excess ofthe amine neat or in a solvent such as water, acetonitrile or a dipolaraprotic solvent at a temperature up to the boiling point of the solvent,e.g. as described hereinafter for reacton (b). Thus, guanidines of thefollowing formula (III): ##STR4## where R^(v), R^(w), R^(x), R^(y) andR^(z) are any of the groups described above for R¹, R² and R³ may beprepared according to the invention. Transformations among guanidinesmay be carried out to achieve the desired substitution as known in theart. For example, if R^(v) and R^(w) are hydrogen while alkyl isdesired, an alkylation reaction may be carried out. A second reaction isa transamination whereby a given --NR^(v) R^(w) group is replaced byanother. Other reactions which can be used to introduce various of the Rgroups in formula (III) are nitration, acylation, cyanation andformylation steps.

The process of the present invention may be employed to preparedguanidine compounds taught in the prior art to have activity, e.g. as H₂-antagonists used for the control of gastric acidity and ulcers.References include U.S. Pat. Nos. 3,950,333; 4,013,659; 4,165,377;4,165,378; 4,242,350; 4,242,351; 4,309,435 and 4,362,728. Many otherguanidine compounds are known in the art and specific examples are asfollows; these and the previously-cited references being incorporated byreference.

    ______________________________________                                        Identity of R.sup.1, R.sup.2 or R.sup.3                                                            Guanidine Final Product                                  (unless otherwise indicated)                                                                       Reference/Utility                                        ______________________________________                                        a.  R.sup.1 and R.sup.3 are                                                                            U.S. Pat. No. 3,352,878                                  independently hydrogen or                                                                          anti-depressant                                          alkyl and when R.sup.1 = H, R.sup.3                                           may be 2-pyridylmethyl which                                                  may be substituted in the                                                     6-position by methyl                                                      b.  3,5-diamino-6-H or halo)-                                                                          U.S. Pat. No. 3,449,341                                  pyrazinimidoyl wherein the                                                                         diuretic                                                 5-amino may be substituted                                                    by C.sub.1-5 alkyl (which may                                                 be substituted with C.sub.1-6                                                 cycloalkyl) or lower alkenyl                                                  and/or by C.sub.1-3 alkyl                                                 c.  2-pyrazinoyl having a wide                                                                         U.S. Pat. No. 3,472,848                                  variety of substituents                                                                            diuretic                                             d.  phenoxyalkyl, where the                                                                            U.S. Pat. No. 4,474,134                                  alkyl is --(CH.sub.2).sub.2 --,                                                                    hypotensive                                              --CH(CH.sub.3)CH.sub.2 --,                                                    --CH.sub.2 CH(CH.sub.3)-- OR --(CH.sub.2).sub.3 --                            and the phenyl group may                                                      be substituted by halogen,                                                    alkoxy, alkyl or nitro                                                    e.  2-monohalogen-substituted                                                                          U.S. Pat. No. 3,506,680                                  benzyl and 2-methylbenzyl                                                                          antihypertensive                                     f.  R.sup.1 and R.sup.3 are both phenyl                                                                U.S. Pat. No. 3,646,029                                  or phenyl substituted by                                                                           control soil borne                                       a single NO.sub.2, 1 or 2 chloro                                                                   pathogenic organisms                                     or 1 or 2 alkyl substituents                                              g.  A benzo[b]thiophen of the                                                                          U.S. Pat. No. 3,855,242                                  formula (R*).sub.m -benzo[b]-                                                                      antimicrobial                                            thiophen-(B).sub.n -where R*                                                  is independently halogen,                                                     C.sub.1-6 alkyl or C.sub.1-6                                                  alkoxy, attached at the 3-                                                    or 5- positions of the benzo-                                                 thienyl nucleus; B is C.sub.1-4                                               alkylene; n = 0 or 1; and                                                     m = 0, 1 or 2.                                                            h.  C.sub.1-8 alkyl; C.sub.5-8 cycloalkyl;                                                             U.S. Pat. No. 3,903,084                                  adamantyl; phenyl(C.sub.1-3)alkyl;                                                                 intermediate (IV)/                                       phenyl; or mono- or  antiarrhythmic                                           di-substituted phenyl or                                                      phenyl(C.sub.1-3)alkyl where the                                              phenyl moiety is substituted                                                  with, same or different,                                                      C.sub.1-3 alkyl, halogen, CF.sub.3                                            or C.sub.1-3 alkoxy.                                                      i.  3-methanesulfonamido-4-hydroxy-                                                                    U.S. Pat. No. 3,903,159                                  phenyl or 3-methanesulfon-                                                                         vasoconstrictor                                          amidophenyl                                                               j.  acetyl; propionyl; or                                                                              U.S Pat. No. 3,914,306                                   phenyl substituted by X.sup.1,                                                                     anti-hypertensive                                        Y.sup.1 and Z.sup.1, where X.sup.1 is                                         hydrogen or halo; Y.sup.1 is                                                  hydrogen, halo, haloloweralkyl,                                               nitro, loweralkyl or loweralkoxy;                                             Z.sup.1 is haloloweralkyl, halo-                                              lowerlkoxy, loweralkylsulfonyl,                                               halo, loweralkoxy, loweralkyl,                                                nitro or cyano, provided X.sup.1 and                                          Y.sup.1 are not both hydrogen at the                                          same time.                                                                k.  (2,6-dihalophenyl)--CH═N--                                                                     U.S. Pat. No. 3,927,096                                                       hypotensives                                         l.  (4-(halo,CH.sub.3,CF.sub.3 or CN)--                                                                U.S. Pat. No. 3,941,825                                  3-(H or Cl)--phenyl)-CH═N--                                                                    anti-protozoal                                       m.  benzyl or β-phenethyl                                                                         U.S. Pat. No. 3,968,243                                                       antiarrhythmia                                       n.  [2-(halo or CF.sub.3)-3,4 or 5-                                                                    U.S. Pat. No. 3,975,533                                  (hydrogen, halogen, CF.sub.3 or                                                                    depression                                               C.sub.1-4 alkyl)-phenyl]-                                                     C(H or C.sub.1-4 alkyl or                                                     C.sub.2-4 alkenyl or C.sub.2-4                                                alkynyl)═N--                                                          o.  3-(hydroxyl, methyl or hydroxy-                                                                    U.S. Pat. No. 4,014,934                                  methyl)-4-hydroxyphenyl                                                                            vasoconstrictor                                      p.  benzyl, p-F--benzyl,p-Cl--benzyl,                                                                  U.S. Pat. No. 4,107,326                                  2,6-diF--benzyl, m-CF.sub.3 --benzyl,                                                              hypotensive, diuretic                                    --CH.sub.2 --C(CH.sub.2 CH.sub.2)phenyl,                                      --CH.sub.2 --C(CH.sub.2 CH.sub.2)-p-F--phenyl,                                --CH.sub.2 --C(CH.sub.2 CH.sub.2)-p-Cl--phenyl,                               --CH.sub.2 --C(CH.sub.2 CH.sub.2)-2,6-diF--                                   phenyl, --CH.sub.2 --C(CH.sub.2 CH.sub.2)--m-                                 CF.sub.3 --phenyl, hydrogen, methyl, ethyl,                                   dimethylaminomethylene or amino.                                          q.  C.sub.1-2 alkyl      U.S. Pat. No. 4,108,859                                                       microbicides                                         r.  (2,6-dimethylphenyl)--CH═N-- or                                                                U.S. Pat. No. 4,154,947                                  (2,6-dichlorophenyl)CH═N--                                                                     hypotensive, diuretic                                s.  2-[(4-methyl-5-imidazolyl)-                                                                        U.S. Pat. No. 4,157,347                                  methylthio]-ethyl or straight                                                                      anti-ulcer                                               or branched alkynyl of 3-9                                                    carbons                                                                   t.  pyrazinecarbonyl with                                                                              U.S. Pat. No. 4,208,413                                  various amino groups at                                                       the 3- and 5-positions.                                                   u.  heterocyclic alkylene where the                                                                    U.S. Pat. No. 4,281,004                                  heterocycle is pyridyl, furyl                                                                      hypoglycemic                                             or thienyl and the alkylene is                                                --(CH.sub.2).sub.1-4 -; or phenyl                                             substituted by hydrogen, F, Cl,                                               Br, CF.sub.3, lower alkyl or lower                                            alkoxy.                                                                   v.  NO.sub.2 ; or (2-(2-pyridylmethyl-                                                                 U.S. Pat. No. 4,289,876                                  thio)ethyl or 3-(2-pyridyl-                                                                        anti-ulcer                                               methylthio)ethyl having no                                                    substitution or hydroxy, cyano,                                               loweralkyl, loweralkoxy,                                                      halogen or amino at the                                                       3-position of the pyridyl                                                     and/or --(CH.sub.2).sub.1-4 NH.sub.2,                                         --(CH.sub.2).sub.1-4 NH(loweralkyl)                                           or --(CH.sub.2).sub.1-4 N(loweralkyl).sub.2                                   at the 6-position of the pyridyl.                                         w.  phenyl or phenyl-substituted by                                                                    U.S. Pat. No. 4,342,764                                  1-3, same or different, of                                                                         hypoglycemic                                             lower aliphatic hydrocarbon                                                   radicals, hydroxy, mercapto,                                                  lower alkoxy, lower alkenoxy,                                                 lower alkylenedioxy, lower                                                    alkylthio, halo, CF.sub.3, NO.sub.2,                                          NH.sub.2, loweralkylamino, di-lower-                                          alkylamino, carboxy or lower-                                                 alkoxycarbonyl.                                                           x.  any organic substituent                                                                            U.S. Pat. No. 4,358,613                                                       phase transfer                                                                catalysts                                            y.  2-nitro-4 or 5-(C.sub.1-6                                                                          U.S. Pat. No. 4,406,893                                  alkylthio)phenyl or a C.sub.1-6                                                                    anthelmintic                                             alkylene terminating with a                                                   COOH, SO.sub.3 H, OSO.sub.3 H, PO.sub.3 H.sub.2                               or OPO.sub.3 H.sub.2 group.                                               z.  Heterocycle--(CH.sub.2).sub.3 NH or                                                                U.S Pat. No. 4,443,375                                   Heterocycle--CH.sub.2 --S--CH.sub.2 CH.sub.2 --                                                    antiulcer                                                where the heterocycle is 4-                                                   imidazolyl, 5-methyl-4-                                                       imidazolyl, 5-ethyl-4-imidazolyl,                                             5-halo-4-imidazolyl, 2-thiazolyl,                                             3-isothiazolyl, 4-halo-3-                                                     isothiazolyl, 2-pyridyl,                                                      3-halo-2-pyridyl, 3-hydroxy-2-                                                pyridyl, 3-hydroxy-2-pyridyl,                                                 3-methoxy-2-pyridyl or 3-ethoxy-                                              2-pyridyl.                                                                aa. R.sup.1 and R.sup.3 combine to form                                                                U.S. Pat. No. 4,443,467                                  dimethylene or trimethylene                                                                        antidiarrhea                                         ab. phenoxypentamethylene wherein                                                                      U.S. Pat. No. 4,491,586                                  the phenyl group is substituted                                                                    anti-ulcer                                               at the 3-position by heterocycle                                              --CH.sub.2 --where the heterocycle                                            is pyrrolidino, piperidino,                                                   hexamethyleneimino, tetra-                                                    hydropyridino or 4-methyl-                                                    piperidino, all being attached                                                by the nitrogen.                                                          ac. R.sup.1 and R.sup.2 may independently                                                              U.S. Pat. No. 4,544,670                                  be hydrogen, alkyl, haloalkyl,                                                                     protozoal infections                                     cycloalkyl, aralkyl, alkenyl                                                                       or gastrointestinal                                      aryl, alkynyl, alkoxy, acyl,                                                                       disorders                                                aroyl, a heterocycle or a                                                     substituted heterocycle or                                                    R.sup.1 and R.sup.2 may together for                                          a 3 to 7 atom ring which may                                                  include 0 to 2 additional hetero                                              atoms of N, O or S.                                                       ad. R.sup.1 and R.sup.2 may independently                                                              U.S. Pat. No. 4,565,826                                  be hydrogen, alkyl, cycloalkyl,                                                                    blood pressure lowering                                  aralkyl, alkenyl, aryl, alkoxy,                                               or a heterocyclic group, or                                                   R.sup.1 and R.sup.2 form a 3 to 7                                             atom ring which may include 0                                                 to 2 additional heteroatoms                                                   of N, O or S.                                                             ae. hydrogen or methyl   Journal of Medicinal                                                          Chemistry, Vol. 10, p.                                                        833-840 (Sept. 1967)/                                                         hypotensive                                          af. hydrogen             J. Med. Chem., Vol.                                                           13, p. 60-63 (Jan.                                                            1970)/hypoglycemic                                   ______________________________________                                    

Example of final products which can be synthesized using the step of thepresent invention are those described in U.S. Pat. No. 3,202,660including the anti-hypertensive clonidine. With R¹ =2,6-dichlorophenyland R² =R³ =H in formula (II), the amidine sulfonic acid is reacted with1,2-diaminoethylene to yield clonidine. Alternatively, if R¹ =H and R²and R³ are --CH₂ CH₂ -- in formula (II), the amidine sulfonic acid (I)can be reacted with 2,6-dichloroaniline to yield clonidine. This samecompound of formula (I) where R² and R³ are joined to form a --CH₂ CH₂-- group can be used to synthesize a variety of drugs by reaction withthe appropriate amine. Such drugs includes tramazoline, U.K. No. 14304as described by M. B. Thomas in DE No. 2,538,620 and by D. Cambridge inthe European Journal of Pharmacol. 72,413 (1981), indanazoline asdescribed in U.S. Pat. No. 3,882,229, tiamenidine, ST 587 (A. De Jongeet al. in Life Sci. 28, 2009 (1981)) where the amine is2-chloro-5-trifluoromethylaniline, benclonidine as described inNetherlands Pat. No. 7608971, and flutonidine (see Chemical Abstracts 68P 39624K (1968) wherein the amine is 2-methyl-5-fluoroaniline.

Another pharmaceutical which can be prepared is the antiviralmoroxydine. Thus, the thiourea H₂ NC(═NH)NHC(═S)NH₂ is the compound offormula (II) and the corresponding sulfonic acid prepared by theinvention process is then reacted with morpholine to yield moroxydine. Ageneral reference for many of such drugs is P. Timmermans et al. inDrugs of the Future, 41 (1984).

Another synthetic route yields the antihypertensive debrisoquin which isformed by first oxidizing thiourea to yield the sulfonic acid (I) whereR¹ =R² =R³ =H followed by reaction with 1,2,3,4-tetrahydroisoquinoline.Another antihypertensive drug is guanethidine which may also be formedby reaction of the sulfonic acid (I) where R¹ =R² =R³ =H, in this casewith 2-(1-N,N-heptamethyleneimino)ethylamine. This same sulfonic acid,also known as aminoiminomethanesulfonic acid, may be used for othermono-substituted guanidines such as guanoxyfen, guanoclor, guanabenz,guanacline, guanazodine, guanisoquin, guanadrel, guanclofine andguanoxan. The single guanidine substituents for each of these, e.g.1-azacyclooct-2-ylmethyl for guanazodine, and for all other knownmono-substituted guanidines are hereby incorporated by reference. FromN,N'-dimethylthiourea starting material of formula (II), one may obtain(methylamino)(methylimino)methanesulfonic acid of the formula (I) whereR¹ =H and R² =R³ =CH₃, which when reacted with benzylamine yieldsbethanidine.

A wide variety of H₂ blockers contining guanidine units and used totreat stomach ulcers can be prepared according to the invention. Acommon feature of many of such drugs is an N-substituted cyano (--CN)group which may be attached to the guanidine with cyanogen bromide asdescribed in references such as Japanese Kokai No. 58/92664 (83/92664)to T. Higashikawa and No. 54/14923 (79/14923) to K. Sirai et al.

It can be seen from the above that a wide variety of guanidines can beprepared with the process of the present invention. Also, the inventioncan be used to snythesize a sulfonic acid of the formula (I) from thecorresponding sulfinic acid.

In particular,N-(1-methyl-2-pyrrolidinylidene)-N'-aryl-4-morpholinecarboximidamides ofthe formula (VIII), including linogliride, may be prepared according tothe following reaction scheme: ##STR5##

In the above formulae, R is phenyl; methylenedioxyphenyl such as 2,3- or3,4-methylenedioxyphenyl; phenyl substituted with 1, 2 or 3 substituentsindependently chosen from the group of halo, such as fluoro, chloro,bromo or iodo, loweralkyl, such as C₁₋₄ alkyl including methyl, ethyland tert-butyl, and lower alkoxy, such as C₁₋₄ loweralkoxy includingmethoxy and ethoxy; or phenyl substituted with a single member of thegroup consisting of dimethylamino, methylethylamino, diethylamino,loweralkanoylamino such as C₁₋₄ alkanoylamino including acetylamino,loweralkylthio such as C₁₋₄ alkylthio including methylthio andethylthio, trifluoromethyl hydroxy, benzyloxy, loweralkanoyloxy such asC₁₋₄ alkanoyloxy including acetoxy, lower alkanoyl such as C₁₋₄ alkanoylincluding acetyl and nitro. Single phenyl substitution may be at the 2,3 or 4 positions while di- and tri-substitution may be at any availableposition with di- and tri-substitution of the same moiety beingpreferred over diverse substitution. In particular, R is phenyl orphenyl substituted by a fluorine atom, e.g. 4-fluoro, or a methyl group,e.g. 2-methyl.

The compound of formula (VII) is a lactam salt of1-methyl-2-pyrrolidinone as described in U.S. Pat. No. 4,211,867. Thelactam fluoroborates of formula (VII), wherein Y is BF₄ ⁻, are generallyknown and may be obtained according to procedures described in theliterature, e.g. see Canadian Pat. Nos. 850,116 and 950,464; U.S. Pat.No. 3,876,658; Ber. 89, Page 2063 (1956); and Org. Synth. 46, 113, 120(1966). The lactam fluorosulfonates of formula (VII), wherein Y⁻ is OSO₄F⁻, are similarly prepared. In general, 1-methyl-2-pyrrolidinone isreacted with an appropriate trialkyloxonium fluoroborate such as (CH₃CH₂)₃ OBF₄ or methyl fluorosulfonated to give the corresponding lactamsalt. The reaction is preferably carried out from 0° C. to ambienttemperature under an inert dry atmosphere (e.g. nitrogen, argon) in aninert anhydrous lower halohydrocarbon solvent such as, for example,chloroform, 1,2-dichloroethane, methylene dichloride (most preferred)and the like. Other inert anhydrous organic solvents that may beemployed include ethers such as, for example, diethyl ether, dioxane,tetrahydrofuran (THF), 1,2-dimethoxyethane and the like; and aromatichydrocarbons such as, for example, benzene, toluene, xylene and thelike. Alternatively, the corresponding 2-loweralkylthiolactim etherswhere X is S-loweralkyl may be prepared by reaction of1-methyl-2-pyrrolidinone with P₂ S₅ according to the procedure of R.Gompper and W. Wiser, Org. Syn., Coll. Vol. V, Pages 780-783, to yield1-methyl-2-pyrrolidinethione. Treatment of this thiolactam withloweralkylating agent such as methyliodide, methyl fluorosulfonate,dimethyl sulfate, methyl tosylate, methyl mesylate, and the like, yieldsthe desired 2-loweralkylthiolactim ethers as the corresponding salts. Analternative method of preparing the formula (VII) compounds is by theinteraction of 1-methyl-2-pyrrolidinone with dimethyl sulfate to givethe corresponding methosulfate salt according to the reaction conditionsdescribed by Bredereck et al., Chem. Ber. 96, 1350 (1963). The reactionis preferably carried out in an anhydrous inert organic solvent such as,for example, an aromatic hydrocarbon, e.g. benzene, toluene, xylene andthe like, an ether e.g. tetrahydrofuran, dioxane and the like, or ahalocarbon, e.g., 1,2-dichloroethane, chloroform and the like. Anothermethod of activating 1-methyl-2-pyrrolidinone is by reaction of themethosulfate salt, i.e., formula (VII) where X is --OCH₃ and Y is OSO₃CH₃ ⁻ with an alkali metal loweralkoxide, preferably sodium methoxide orsodium ethoxide in the corresponding loweralkanol solvent, according tothe reaction conditions described by H. Bredereck, et al., Chem. Ber.,97, 3081-3087 (1964), to yield the corresponding lactam acetal. Anotherexample of an activated lactam of formula (VII) is the chloride saltwherein X is Cl and Y is Cl⁻. The chloride salts are readily obtained byactivation of 1-methyl-2-pyrrolidinone with phosgene (ClCOCl) or thionylchloride (SOCl₂) according to the directions of W. Jentzsch and M.Seefelder, Chem. Ber., 98, 274 (1965), with the evolution of CO₂ or SO₂,respectively.

In the invention oxidation, thiourea (II), e.g. the N-arylthiourea offormula (IV), in step (a), is oxidized to acid (I), e.g. theN-arylformamidinesulfonic acid of formula (V) with hydrogen peroxide inthe presence of a molybdenum catalyst, e.g. a molybdenum (VI) catalyst.During the reaction, the oxidation state of the Mo will vary asevidenced by color changes. Thus, when an Mo (VI) catalyst is used asthe added catalyst material, the oxidation state will change during thereaction, e.g. (VI) to (III) to (O). The invention comprises all of suchmolybdenum catalysts. The exact role of each oxidation state in thereaction is not clear. The catalyst to be added is, in particular, amolybdate of the formula QMoO₄ wherein Q is two ions having a +1 valenceor one ion having a +2 valence. Specific examples of molybdenumcatalysts include H₂ MoO₄, (NH₄)₂ MoO₄ or Na₂ MoO₄. Such catalystsincludes hydrates and other solvates, e.g. Na₂ MoO₄ ·2H₂ O and H₂ MoO₄·H₂ O. It has been found that superior yields of final and intermediateproducts are obtained by conducting the oxidation with a molybdenum (VI)catalyst as opposed to other catalysts which may be considered to beequivalents, e.g. tungsten or chromium. General literature referencesfor similar catalytic systems include: F. Difuria, G. Modena, Rev. Chem.In. (1985) 6, 51; R. A. Sheldon & J. K. Kochi "Metal CatalyzedOxidations of Organic Compounds" Academic Press, N.Y. 1981; D.DeFilippo, E. F. Trogu, JCS Perkin II (1972) 1500. Hydrogen peroxide isused in the oxidation as an aqueous solution such as a 10 to 90% byweight solution, e.g. a 30% solution although other peroxide sourcessuch as peracetic acid can be used.

The oxidation requires slightly more than about 3 equivalents of H₂ O₂and the reaction may be carried out at about 0° to 80° C. Preferably,the reaction is carried out in two stages which are:

(i) during addition of the hydrogen peroxide at a temperature of about0° to 15° C., and

(ii) after addition of the hydrogen peroxide at a temperature of about15° to 80° C.

The oxidation gives the best results when the temperature of theaddition of H₂ O₂ is from about 5° to 10° C. The rate of addition of H₂O₂ can usually be increased once about 2/3 of the H₂ O₂ has been added.During the peroxide addition, it is normal to observe color changes ofthe reaction mixture from white to green or blue.

After addition of the H₂ O₂, the temperature may be allowed to rise bythe exotherm of the reaction to a maximum of about 80° C. during whichthe color will revert to an off-white color. Preferably, the maximumtemperature is about 60° C. or most preferably about 40° C. In amodification of this procedure, the first two equivalents of the H₂ O₂are added to about 0° to 15° C., the cooling bath is removed and thetemperature is allowed to rise to about 20° to 50° C., e.g. about 40° C.with the final equivalent being added at a rate to maintain thetemperature at about 40° C.

Sodium chloride or other inert salts may be added to the reactionmixture to prevent freezing.

The starting material thiourea of formula (IV) may be obtained byreaction of the corresponding aryl isothiocyanate with ammonia asdescribed by A. W. Hoffman in J. Fortschrite Chemie 349 (1858) and Comp.Rend., 47 424 as described in Beilstein Hauptwerke, Volume 12, page 454.The arylisothiocyanates of the formula R--N═C═S, many of which areknown, may be prepared according to the extensive processes reported inthe literature for making isothiocyanates. For example, they may beobtained from the methodologies reported by M. Bogemann et al. in"Methoden der Organische Chemie Houben-Weyl", Eugen Muller (Ed.), GeorgThieme Verlag (Publi.) Stuttgart, Germany, Vol. 9, pages 867-884 (1955);"Preparation des Isothiocyanates Aromatiques" by A. Rasschaert et al.,Ind. Chim., Belge, 32, 106 (1967); German Pat. No. 1,300,599; J. Org.Chem., 36, 1549 (1971); U.S. Pat. Nos. 2,395,455 and 3,304,167; FrenchPat. No. 1,528,249; "A New Synthesis of Aliphatic isothiocyanates",Angew. Chem. Internat. Ed., 6, 174 (1967); Bull. Chem. Soc. Japan, 482981 (1975); Tetrahedron. 29, 691 (1973); Chem. Ber., 101, 1746 (1968);and J. Indian Chem. Soc. 52, 148 (1975).

In step (b), the N-arylformamidinesulfonic acid of formula (V) isreacted with morpholine or an activated form of morpholine such asmorpholine acetate. An advantage of the process of the inventioncompared to the use of the corresponding N-arylformamidinesulfinic acidis that the sulfinic acid (--SO₂ H) requires that an activated form ofmorpholine be used, e.g. morpholine acetate, or morpholine with an acidcatalyst. This, of course, necessitates an extra synthetic step in thereacton of commercially available morpholine to its activated form orthe use of an extra reagent. Thus, a preferred aspect of the inventionstep (a) is the production of a sulfonoic acid which, in the subsequentstep (b), allows reaction with the less expensive reactant morpholine.The use of morpholine also results in a higher yield.

The reaction of the sulfonic acid of formula (V) with morpholine may becarried out with a molar excess of morpholine using morpholine itself asthe solvent. Thus, use of the sulfonic acid (V) allowing morpholine asthe reagent, results in another economy in the overall process. Thereaction temperature may be about 15° to 100° C., depending on theparticular reactants, with stirring and a co-solvent such asacetonitrile or water may be added to aid such stirring. The co-solventshould be inert to the reactants.

Step (c) is carried out as described in U.S. Pat. No. 4,211,867. Inparticular, one may use stochiometric quantities of the salt of formula(VII) and the carboximidamide of formula (VI). Suitable anhydrousorganic solvents for conducting the reaction include anhydrous aproticsolvents, e.g., ethers, such as, for example, diethylether,tetrahydrofuran, dioxane and the like; lower halogenated hydrocarbons,such as, for example, chloroform, methylene chloride, 1,2-dichloroethaneand the like; and aromatic hydrocarbons, such as, for example, benzene,toluene, xylene, and the like. Ambient to 0° C. or higher temperaturemay be employed depending on the particular reactants. The product(VIII) in the form of the corresponding HY salt, is converted to thecorresponding base form, by conventional means, for example, bytreatment with a suitable alkali such as alkali metal or alkaline earthmetal hydroxides; carbonates and the like. In particular, a temperatureof about 25° to 100° C. may be used when the salt (VII) is themethosulfate salt obtained from 1-methyl-2-pyrrolidinone and dimethylsulfate. Another method of preparing the formula (VIII) compounds is bythe interaction of the guanidine precursor (VI) with a chloride salt offormula (VII) in an anhydrous aprotic solvent, such as, for example, anether, e.g. diethyl ether, dioxane, THF and the like, a halohydrocarbon,e.g. chloroform, methylene chloride, 1,2-dichloroethane and the like,and, preferably, an aromatic hydrocarbon, e.g. benzene, toluene, xyleneand the like.

It has suprisingly been found that the reaction of the thiourea (II) or(IV) to yield the amidine sulfonic acid (I) or (V) is assisted by theintroduction of ultraviolet visible light or an aliquot of reactionmixture which itself has been subjected to light. In particular, thereaction does occur in the dark--however, a great exotherm is observed.The introduction of light or light-treated reaction mixture minimizesthis exotherm. This aspect of the invention was recognized duringscaling up work on the reaction of formula (IV) to yield (V) whererelatively large volume glass-lined vessels were used in place of thebench-scale work on the reaction which had been done with glass vessels.Such observations are in agreement with the photosensitivity ofpolyoxometalates recently reported by Craig L. Hill et al. in J. Am.Chem. Soc., 1985, Vol. 197, pages 5148-5157.

In the following Examples and throughout the specification, thefollowing abbreviations may be used: mg (milligrams); g (grams); Kg(kilograms); ml (milliliters); tlc (thin layer chromatography); RT (roomtemperature); eq (equivalents); L (liter); ir (infrared); m (moles);;mmole (millimoles); ˜ (about); min (minutes); hr (hours); IPA (isopropylalcohol); M (molar); N (normal); mp (melting point); bp (boiling point);MeOH (methanol); IPA (isopropanol); EtOH (ethanol); HOAc (acetic acid);and C, H, N, O, etc. (the chemical symbols for the elements). Unlessotherwise indicated, all temperatures are reported in ° C. (degreescentigrade) and, all references to hydrogen peroxide in aqueous hydrogenperoxide and all references to ether are to diethyl ether.

EXAMPLE A

i. Formula (V): R=phenyl

N-phenylthiourea (2.0g, 0.013m), sodium tungstate dihydrate (0.008g,0.00002m), and sodium chloride (0.25g), were suspended in water (10ml)and cooled to 0°-5° C. using an ice/salt bath. Aqueous hydrogen peroxide(4.5ml, 0.044m, 30%) was added at a rate to keep the temperature lessthan 10° C. Once the addition was complete, the ice bath was removed andthe reaction was allowed to exotherm to 35° C. and the temperature wascontrolled between 30°-35° C. with an ice bath. Once the exotherm wascomplete, the reaction was stirred at ambient temperature for 30 min andthen cooled and filtered. Teh filter cake was washed once with 2ml ofice water. There was thus obtained 1.47g of the sulfonic acid of Formula(V) where R=phenyl (56.3%). The ir spectra corresponded to that ofdesired product.

ii. Formula (VI): R=phenyl

The sulfonic acid product of Example Ai (1.46g) was added to morpholine(1.3g, 0.015m) in acetonitrile (9ml). The reaction exothermed to 35° C.The reaction was then warmed to 50°-60° C. for 30 min. During this timethe reaction became homogeneous. The reaction mixture was concentratedand treated with 3N NaOH until very basic. The precipitate was isolatedby filtration. There was obtained 1.38g of the product of Formula (VI)where R=phenyl as a white solid (52%). The white solid was 80.6% purewhich translates to a 41.9% yield of pure product.

EXAMPLE 1

This example was conducted in a side-by-side manner with Example A usingidentical conditions:

a. Formula (V): R=phenyl

N-phenylthiourea (2g, 0.013m), sodium molybdate dihydrate (0.005g,0.00002m), and sodium chloride (0.25g), were suspended in water (10ml)and cooled to 0°-5° C. using an ice/salt bath. Aqueous hydrogen peroxide(4.5ml, 0.044m, 30%) was added at a rate to keep the temperature lessthan 10° C. Once the addition was complete, the ice bath was removed andthe reaction was allowed to exotherm to 35° C. and the temperature wascontrolled between 30°-35° C. with an ice bath. Once the exotherm wascomplete, the reaction was stirred at ambient temperature for 30 minthen cooled and filtered. The filter cake was washed once with 2ml ofice water. There was obtained 1.87g of the sulfonic acid of Formula (V)where R=phenyl (71.6%). The ir spectra corresponded to that of desiredproduct.

b. Formula (VI): R=phenyl

The sulfonic acid product of Example 1a (1.86g) was added to morpholine(1.3g, 0.015m). During the addition the reaction mixture became verythick therefore, acetonitrile (9ml) was added. The reaction exothermedto 35° C. The reaction was then warmed to 50°-60° C. for 30 min. Duringthis time, the reaction became homogeneous. The reaction mixture wasconcentrated and treated with 3N NaOH until very basic. The precipitatewas isolated by filtration. There was obtained 1.7g of the product offormula (VI) where R=phenyl as a white solid (65% yield). The yield ofpure product, i.e., when adjusted for purity, was 55.6%.

EXAMPLE 2

a. Formula (V): R=phenyl

In a 3-neck round bottom flask (equipped with an ice/salt bath, athermometer, dropping funnel and a mechanical stirrer), N-phenylthiourea(1520g, 10.0m), sodium molybdate dihydrate (10.0g, 0.04m), sodiumchloride (700g, 12m) were suspended in 7000 ml of water and cooled to 0°C. Hydrogen peroxide (30%, 3.6Kg, 31.8m) was added dropwise at a rate tomaintain the temperature between 0°-15° C. Once the addition wascomplete, the cooling bath was removed and the reaction was warmed to15° C. The reaction was then permitted to exotherm to 45° C. at whichtime a cooling bath was applied to control the exotherm (reactioncontinued to exotherm to 70° C.). Once the reaction exotherm wascomplete, the reaction was cooled to about 10° C. and filtered. Thefilter cake was washed with a small amount of ice water. The sulfonicacid product (V) was obtained as an off-white solid, mp 155°-157° C.

b. Formula (VI): R=phenyl

In a 3-neck round bottom flask (equipped with a mechanical stirrer and athermometer), morpholine (1040g, 12m) was treated with the sulfonic acidprepared in Example 2a.

The resulting slurry was stirred for 30-40 min during which time itexothermed to 102° C. If the temperature of the reaction does not reach100° C., heat should be applied until the reaction temperature is about100° C. Once the reaction reaches this temperature, the reaction isconsidered complete. Once the reaction temperature dropped to 50° C.,warm water was added and the reaction was treated with charcoal andfiltered. The mother liquor was treated with NaOH (50%, 1280g, 16m,diluted to 20% with ice). Upon vigorous stirring, a white semi-solidprecipitated from the solution. Once the product was filtered, it wasdissolved in CH₂ Cl₂ and any water present was separated. The organiclayer was dried over anhydrous MgSO₄ and concentrated in vacuo. Themixture was filtered and the filter cake was washed with water. Theproduct was isolated as a white solid in a 56% (1117g) yield fromphenylthiourea. The yield reported is based on the product isolatedafter the water was removed.

EXAMPLE 3

a. Formula (V): R=phenyl

In a 12L 3-neck round bottom flask (equipped with an ice/salt bath, athermometer, dropping funnel and a mechanical stirrer), N-phenylthiourea(734g, 4.8m), sodium molybdate dihydrate (5.0g, 0.021m), and sodiumchloride (260g, 4.5m) were suspended in 2.5L of water and cooled toabout 0° C. Hydrogen peroxide (30%, 1710g, 15.1m) was added dropwise ata rate to maintain the temperature between 0°-9° C. Once the additionwas complete, the cooling bath was removed and the reaction slowlyexothermed. The temperature of the reaction was controlled at about 35°C. with a cold water bath. Once the reaction exotherm was complete, thereaction was cooled to 10° C. and filtered. The filter cake was washedwith a small amount of ice water. The sulfonic acid product was obtainedas an off-white solid in 80% yield (766g).

b. Formula (VI): R=phenyl

In a 12L 3-neck round bottom flask (equipped with a mechanical stirrer,a thermometer, and a cooling bath), morpholine (541g, 6.3m) in 3.5L CH₃CN was cooled and treated with glacial acetic acid (378g, 6.3m). Theresulting slurry was cooled to 10° C. and the sulfonic acid prepared inExample 3a was added in one portion. In contrast to morpholine, theaddition of the sulfonic acid to morpholine acetate is endothermic. Oncethe sulfonic acid was added, the cooling bath was removed. The reactionwarmed to ambient temperature and once all of the solid had gone intothe solution, the reaction was complete. The reaction was thenconcentrated to remove the CH₃ CN. NaOH (50%, ˜6.3m) was diluted with1.5L of ice and added to the concentrate until the concentrate wasneutral. The aqueous mixture was then extracted with ether and the etherphase was discarded. The aqueous phase was then treated with aqueousNaOH until very basic. A white solid precipitate from the solution. Thesolution was cooled, filtered and washed with water. The product wasisolated as a white solid in a 58% yield from phenylthiourea.

EXAMPLE 4

a. Formula (V): R=phenyl

In a 1-liter Morton flask, (equipped with a mechanical stirrer andthermometer, cooled by a water/salt bath) 1-phenyl-2-thiourea (75g,0.49m) and sodium molybdate dihydrate (0.19g, 0.0008m) were suspended in300ml distilled water and cooled to 0° C. Hydrogen peroxide (113ml,1.1m, 30%) was added dropwise at a rate to maintain the temperaturebelow 5° C. Use of a Morton flask is recommended due to the ease intemperature control it provides. The reaction is initiated with a fewmilliliters of peroxide; once an exotherm or a color change (white toblue or green) is observed, addition of peroxide may continue. Theaddition of the first half of the peroxide is very exothermic; however,the addition of the second half is only mildly exothermic. For asuccessful experiment it is preferred that the temperature not exceed 5°C.; exotherms above about 10° C. result in impurities. Once the additionwas complete, the reaction was stirred at 0°-10° C. for an additional3.5-4.5 hr. The reaction was filtered and the filter cake was washed twotimes with a small amount of ice water. The acid product was obtained asa lightly colored solid and was used below as a wet cake.

b. Formula (VI): R=phenyl

In a 1-liter 3-neck round bottom flask, morpholine (87.12g, 1.0m) in600ml acetonitrile was cooled and treated with glacial acetic acid(60.05g, 1.0m). The resulting slurry was cooled to about 10° C. and thesulfinic acid product of Example 4a was added in an endothermicreaction. The reaction mixture was stirred and allowed to warm to roomtemperature overnight. The reaction was checked by tlc (95:5:5;MeOH:CHCl₃ :HOAc; silica gel) and cooled to about 0° C. A white solid(morpholine acetate) precipitated and this was isolated by filtration.The filter cake was washed twice with a small amount of coldacetonitrile. The filtrate was concentrated (using a 30° C. bath orcooler) to approximately half the original volume (recovered 450mlsolvent) and then was treated with 25% NaOH until basic. The mixture(add water until all solid is in solution) was extracted 3 times (150mleach) with methylene chloride; the organic phase was then washed withwater (50ml), dried over anhydrous Na₂ SO₄, and concentrated. There wereobtained 68g (68% yield) of product based on phenylthiourea.

EXAMPLE 5

Formula (VIII): R=phenyl (linogliride fumarate)

In a 200ml round bottom flask, N-methylpyrrolidinone (15.6g, 0.16m) wastreated with dimethyl sulfate (17.93g, 0.14m) and heated on a steam bathfor 45 min. The reaction was cooled slightly.N-phenyl-1-morpholinecarboximidamide (14.11g, 0.068m) was dissolved in60ml hot methylene chloride and added to the complex formed above withstirring. A mild exotherm resulted. The reaction was heated at refluxfor half an hour. A check by tlc (silica gel: 95:5:5, MeOH:CHCl₃ :HOAc)showed no starting material remained. The reaction was quenched into250ml 3N NaOH, extracted 3 times with 50ml CH₂ Cl₂, dried over anhydrousK₂ CO₃ and concentrated to obtain the free base as a light brown/yellowoil. Fuamric acid (8.6g, 0.074m) was dissolved in 90ml refluxingisopropanol. The free base prepared above was dissolved in 25mlisopropanol and added to the fumaric acid with vigorous stirring. Thesolution was stirred and allowed to cool gradually to RT. A whiteprecipitate formed which was collected by filtration. The filter cakewas washed 2 times with a small amount of cold isopropanol. The product,linogliride fumarate, was obtained in an 86.5% yield as a white solid,mp 172°-175° C., softening at 165° C.

EXAMPLE 6

a. Formula (V): R=4-fluorophenyl

4-fluorophenyl-2-thiourea (2.0g, 0.0118m) produced using a modifiedmethod of R. L. Frank et al. in Org. Syn., Collected Vol. 8, 735 (1955)and sodium molybdate dihydrate (0.004g, 0.000016m) were suspended in10ml of water. Hydrogen peroxide (3.6ml, 30%, 0.035m) was added dropwiseat a rate to keep the temperature between 20°-25° C. Once the additionof the peroxide was complete, the cooling bath was removed and thereaction was allowed to exotherm to 28° C. The reaction was stirred forapproximately six hours after which time it was cooled and filtered. Thesulfonic acid product was obtained as a gray/brown solid in a 47% yield(mp 150° C. decomposition with gas evolution).

b. Formula (VI): R=4-fluorophenyl

The sulfonic acid product of Example 6a (1.0g, 0.0046m) was added tomorpholine (0.96g, 0.011m) and acetic acid (0.67g, 0.011m) in 8mlacetonitrile at 5° C. The addition was endothermic and upon addition ofthe sulfonic acid, the reaction mixture turned purple. Within 1-2 min,the reaction turned bright blue. The ice bath was removed and thereaction sat overnight at RT. The reaction was treated with 3N NaOHuntil very basic then extracted with CHC1₃, the organic phase was driedand concentrated. The resulting green/brown oil crystallized to a solidupon storing at 0° C. The solid was suspended in water and filtered toyield 0.85g (83% yield from sulfonic acid) of the desired product as agray solid, mp 100° C. (soft) 105°-108° C. melt.

c. Formula (VIII): R=4-fluorophenyl

N-methylpyrrolidinone (0.38g, 0.0038m) was treated with dimethylsulfate(0.38g, 0.003m) and heated on a steam bath for 45 min. The guanidineproduct of Example 6b (0.5g, 0.0024m) was dissolved in 5ml of CH₂ Cl₂with gentle warming and added to the complex formed above. The reactionmixture was stirred without external heat for 1.5 hr (tlc showedreaction complete). The reaction was quenched into 3N NaOH and extractedthree times with CH₂ Cl₂, dried over anhydrous K₂ CO₃ and concentrated.Fumaric acid (0.3g, 0.0026m) was dissolved in 7ml refluxing IPA and wastreated with the above isolate (dissolved in 3ml IPA). The fumarate saltwas obtained as a white solid in 70% yield (mp 170°-175° C.).

EXAMPLE 7

a. Formula (V): R=2-methylphenyl

2-Methylphenyl thiourea (8.6g, 0.05m) and sodium molybdate dihydrate(0.02g, 0.00008m) were suspended in 30ml of water. Hydrogen peroxide(30%, 16ml, 0.157m) was added dropwise at a rate to maintain thetemperature between 20°-25° C. (cooling bath was used). Once theaddition was complete, the reaction exothermed to 28° C. then cooledback to RT. The reaction sat at RT overnight. The reaction was cooledand filtered. The sulfonic acid product was obtained as a light bluesolid in a 69% yield (mp 189°-192° C.).

b. (Formula (VI): R=2-methylphenyl

The sulfonic acid product of Example 7a (3.0g, 0.014m) was added tomorpholine (2.4g, 0.027m) in 20ml CH₃ CN at RT. The reaction mixture washeated at 45° C. for 1 hr. The reaction was treated with 3N NaOH untilvery basic and extracted with ether and methylene chloride, dried andconcentrated. A clear viscous liquid was obtained which solidified to awhite semi-solid. 1.9g of the desired product was obtained (62% yield).

c. Formula (VIII): R=2-methylphenyl

N-methylpyrrolidinone (1.1g, 0.011m) was treated with dimethylsulfate(1.18g, 0.009m) and heated on a steam bath for 40 min. The guanidineproduct of Example 7b (1.5g, 0.007m) was dissolved in 10ml of CH₂ Cl₂and added to the complex at RT. The addition was exothermic and thereaction was complete within 0.5 hr. The reaction was quenched with 3NNaOH and extracted 3 times with CH₂ Cl₂, dried and concentrated. Fumaricacid (0.95g, 0.008m) was dissolved in 10ml refluxing IPA and treatedwith the isolate (dissolving in 2ml IPA). The final product was obtainedin 48% yield as a white crystalline solid, mp 155°-157° C. withdecomposition and gas evolution.

EXAMPLE 8

Formula (I): R¹ =R² =H; R³ =n--C₃ H₇

In a manner similar to Example 4 the sulfonic acid of Formula (I) wasprepared where R¹ =R² =H and R³ =C₃ H₇.

1-Propyl-2-thiourea (1.54g, 0.013m), sodium molybdate dihydrate (0.005g,0.00002m), and sodium chloride (0.25g), were suspended in water (3ml)and cooled to 0°-5° C. Aqueous hydrogen peroxide (4.5ml, 0.044m, 30%)was added at a rate to keep the temperature less than 10° C. Once theaddition was complete, the ice bath was removed and the reaction wasallowed to exotherm to 40° C. and the temperature was controlled between35°-40° C. with an ice bath. Once the exotherm was complete, thereaction was cooled to 5° C. and filtered. There was obtained 1.21g (mp179°-182° C., dec.) of the sulfonic acid of formula (I) where R¹ =R² =Hand R³ =n-propyl (56%). The ir spectra corresponded to the S-trioxidederivative.

EXAMPLE 9

Synthesis of Guanethidine

2-(Octahydro-1-azocinyl)ethylamine (0.013m) is reacted withaminoiminomethanesulfonic acid (0.013m); the reaction is followed bytlc. After completion of the reaction, the mixture is basified andextracted with methylene chloride several times. The organic phase isdried and evaporated to give the product free base.

EXAMPLE 10

Synthesis of Debrisoquin

Tetrahydroisoquinoline (0.013m) is treated withaminoiminomethanesulfonic acid (0.01m) at ambient temperature. Aftercompletion of the reaction, it is diluted with acetonitrile, cooled andthe solid product is collected by filtration.

EXAMPLE 11

Synthesis of Moroxydine

Amidinothiourea (2.36g, 0.02m) was suspended in 5 ml of water. Sodiummolybdate dihydrate (0.012g, 0.00005m) and about 1.5g of sodium chloridewere added. The solution was cooled to 0° C. and 30% hydrogen peroxide(8.4ml, 0.08m) was added dropwise: addition of the first 2.5 ml was veryexothermic, dropwise addition required about 45 min. After addition ofthe second eq, the reaction mixture was allowed to warm to 14°-16° C.,at which point the mixture exothermed to 50°-60° C. After cooling to 5°C., the third eq of peroxide was added dropwise; no exotherm was noted.Further cooling afforded a precipitate which was air dried and thenplaced under high vacuum to give 1.4g, mp 158°-170° C.

Oxidized amidinothiourea (0.34g, 0.002m) is added to morpholine (0.34g,0.004m) and the reaction stirs overnight at ambient temperature. It ischecked by tlc (silica gel; 95:5:5::MeOH:HOAc:CHCl₃) and allowed toproceed until complete. The reaction mixture is treated with sodiumhydroxide, and then is extracted several times with methylene chloride.The organic extracts are combined, dried and concentrated to yield0.15-0.45g moroxydine free base.

EXAMPLE 12

Synthesis of Flutonidine

Ethylenethiourea (1.3g, 0.013m), sodium molybdate dihydrate (0.0125g,0.05mmol) and sodium chloride (0.5g) were stirred together in 5ml waterat 0° C. Hydrogen peroxide (30%, 2.6ml, 0.025m) was added dropwise attemperatures between -5° C. and 3° C.; color changes were notedthroughout the addition. The third eq (1.31ml) was added at 10°-25° C.The reaction mixture was cooled to 5° C.; a white solid was filtered anddried. The solid (1.45g, mp 140°-145° C.(d)) was identifiedspectroscopically as the S-trioxide derivative.

Ethylenethiourea-S-trioxide (0.55g, 0.0037m) was added to5-fluoro-2-methylaniline (0.91g, 0.0074m) in 2ml water and 3mlacetonitrile at ambient temperature. The reaction was heated for 2.25hours at 40°-70° C. The reaction was concentrated, treated with sodiumhydroxide and extracted with methylene chloride. The organic extractswere dried and concentrated to yield 0.7g of an oil which was identifiedas the title product by spectroscopic methods.

EXAMPLE 13

Synthesis of Clonidine

2,6-Dichlorophenylthiourea (2.87g, 0.013m), sodium molybdate dihydrate(0.0125g, 0.00005m), and sodium chloride (0.5g) were stirred together in5ml water and cooled to 0° C. In the presence of ordinary laboratorylight, hydrogen peroxide (30%, 4.2ml, 0.04m) was added dropwise. Thefirst equivalent was added at 5° C.; the second was added between15°-25° C. and the third was added between RT and 40° C. When theoxidation was complete, the suspension was cooled and the solid wasfiltered. After drying, the solid (2.7g, 77%, mp 188°-190° C.(d)) wascharacterized spectroscopically as the S-trioxide derivative of thestarting thiourea.

2,6-dichlorophenylsulfonic acid (1.0g, 0.0037m) was added toethylenediamine (0.5g, 0.008m) in the absence of solvent. The reactionexothermed to 35° C. and was diluted with acetonitrile and heated at 65°C. for 7.25 hr. The reaction was concentrated, treated with sodiumhydroxide and extracted with methylene chloride. The organic phase wasdried and concentrated to yield 0.5g of clonidine. The product wasidentified by spectroscopic methods.

What is claimed is:
 1. A method for the synthesis of an amidine sulfonicacid of the following formula (I): ##STR6## wherein R¹, R² and R³ areindependently hydrogen, NH₂, perhaloalkyl, perhaloaryl, NO₂, an organicgroup or are joined to form an organic group, which comprises oxidizinga thiourea of the following formula (II): ##STR7## with hydrogenperoxide by the addition of a molybdenum (VI) catalyst and ultravioletvisible light or an aliquot of reaction mixture which itself wassubjected to ultraviolet visible light for a time sufficient to initiatethe oxidation.
 2. The method of claim 1, wherein R¹ is hydrogen.
 3. Themethod of claim 1, wherein R¹ and R² are hydrogen.
 4. The method ofclaim 1, wherein R¹, R² and R³ are hydrogen.
 5. The method of claim 1,wherein R¹ and R³ are hydrogen.
 6. The method of claim 1, wherein R¹ ishydrogen and R² and R³ are joined to form a substituted or unsubstituteddimethylene or trimethylene group.
 7. The method of claim 1, whereinsaid organic group is alkyl, substituted alkyl, cyclic alkyl,substituted cyclic alkyl, aryl, substituted aryl, heterocyclic orsubstituted heterocyclic.
 8. The method of claim 1, wherein said addedmolybdenum catalyst is a molybdate of the formula QMoO₄ where Q is twoions having a +1 valence or one ion having a +2 valence.
 9. The methodof claim 8, wherein said added molybdenum catalyst is QMoO₄ and Q is(NH₄)₂, H₂ or Na₂.
 10. The method of claim 9, wherein said addedmolybdenum catalyst is Na₂ MoO₄ ·2H₂ O.
 11. The method of claim 1,wherein said oxidizing is conducted in the presence of ultravioletvisible light.
 12. The method of claim 1, wherein said oxidizing isconducted in the presence of seed reaction mixture which had beenexposed to ultraviolet visible light for a time sufficient to initiatethe oxidation.
 13. The method of claim 1, wherein said oxidizing isconducted in a vessel which is closed to ultraviolet visible light.